Project Summary Disruption of aortic homeostasis arising from genetic defects or exposure to environmental risk factors leads to localized abnormal widening of the aorta, a degenerative disease state termed aortic aneurysm (AA). Experimental studies reveal that AA is associated with compromised smooth muscle contractility, extracellular matrix (ECM) deterioration, and increased vascular inflammation associated with leukocyte infiltration. This pathologic state culminates with weakening of the vessel wall and progressive dilatation that, if left untreated, results in an often fatal dissection and/or rupture. Despite the high degree of morbidity and mortality associated with aortic aneurysm, medical treatments remain inadequate and urgent surgery is unfortunately the top therapeutic option. Therefore, it is imperative to address this important unmet clinical need, potentially by the development of novel pharmacologic therapies as well as more effective management strategies to combat this dreadful disease. However, a critical roadblock lies in the incomplete understanding of the molecular mechanisms governing AA formation and progression. To that end, this project seeks to develop a promising group of therapeutic agents termed small molecule activators of Protein Phosphatase 2A (SMAPs) for the treatment of aortic aneurysm and gain mechanistic insights into the role of PP2A in the pathogenesis of this disease. Reversible protein phosphorylation plays a ubiquitous cellular regulatory role in biological functions. The regulation of protein phosphorylation involves a balance between the activities of both protein kinases and protein phosphatases. Although there is a significant understanding of how aberrant kinase activity contributes to human cardiovascular disease, the regulation and therapeutic potential of phosphatases in this area remains under-explored. Protein phosphatase 2A (PP2A) is a holoenzyme with notable serine/threonine phosphatase activity in mammalian cells. Restoration of PP2A activity has been shown to be of significant therapeutic value, however pharmaceutically tractable approaches to directly activate PP2A remain elusive. Recent observations from our laboratory revealed that a profound loss of PP2A activity in both human and mouse aortic aneurysmal tissues. Furthermore, administration of the orally bioavailable small molecule activator of PP2A (SMAPs), markedly suppressed AA progression in both Marfan's syndrome (MFS) and angiotensin II- (Ang II) induced abdominal aortic aneurysm (AAA) in animal models. These observations provide the basis for the two main hypotheses for this application: (1) PP2A inactivation is involved in aortic aneurysm (AA) etiology and (2) activation of PP2A may serve as a novel strategy to limit AA progression. In this proposal, we will leverage both pharmacologic and genetic approaches to dissect the molecular basis and functional consequences of PP2A activation/inactivation on aortic aneurysm.